TFEB controls sensitivity to chemotherapy and immuno-killing in non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC) the efficacy of chemo-immunotherapy is affected by the high expression of drug efflux transporters as ABCC1 and by the low expression of ABCA1, mediating the isopentenyl pyrophosphate (IPP)-dependent anti-tumor activation of Vγ9Vδ2 T-lymphocytes. In endothelial cells ABCA1 is a predicted target of the transcription factor EB (TFEB), but no data exists on the correlation between TFEB and ABC transporters involved in the chemo-immuno-resistance in NSCLC. METHODS: The impact of TFEB/ABCC1/ABCA1 expression on NSCLC patients' survival was analyzed in the TCGA-LUAD cohort and in a retrospective cohort of our institution. Human NSCLC cells silenced for TFEB (shTFEB) were analyzed for ABC transporter expression, chemosensitivity and immuno-killing. The chemo-immuno-sensitizing effects of nanoparticles encapsulating zoledronic acid (NZ) on shTFEB tumors and on tumor immune-microenvironment were evaluated in Hu-CD34+ mice by single-cell RNA-sequencing. RESULTS: TFEBlowABCA1lowABCC1high and TFEBhighABCA1highABCC1low NSCLC patients had the worst and the best prognosis, respectively, in the TCGA-LUAD cohort and in a retrospective cohort of patients receiving platinum-based chemotherapy or immunotherapy as first-line treatment. By silencing shTFEB in NSCLC cells, we demonstrated that TFEB was a transcriptional inducer of ABCA1 and a repressor of ABCC1. shTFEB cells had also a decreased activity of ERK1/2/SREBP2 axis, implying reduced synthesis and efflux via ABCA1 of cholesterol and its intermediate IPP. Moreover, TFEB silencing reduced cholesterol incorporation in mitochondria: this event increased the efficiency of OXPHOS and the fueling of ABCC1 by mitochondrial ATP. Accordingly, shTFEB cells were less immuno-killed by the Vγ9Vδ2 T-lymphocytes activated by IPP and more resistant to cisplatin. NZ, which increased IPP efflux but not OXPHOS and ATP production, sensitized shTFEB immuno-xenografts, by reducing intratumor proliferation and increasing apoptosis in response to cisplatin, and by increasing the variety of anti-tumor infiltrating cells (Vγ9Vδ2 T-lymphocytes, CD8+T-lymphocytes, NK cells). CONCLUSIONS: This work suggests that TFEB is a gatekeeper of the sensitivity to chemotherapy and immuno-killing in NSCLC, and that the TFEBlowABCA1lowABCC1high phenotype can be predictive of poor response to chemotherapy and immunotherapy. By reshaping both cancer metabolism and tumor immune-microenvironment, zoledronic acid can re-sensitize TFEBlow NSCLCs, highly resistant to chemo- and immunotherapy.

Hormonal Agents in Localized and Advanced Prostate Cancer: Current Use and Future Perspectives.

Prostate cancer (PC) is generally a hormone-dependent tumor. Androgen deprivation therapy ( has been the standard of care in metastatic disease for more than 80 years. Subsequent studies have highlighted the efficacy of ADT even in earlier disease settings such as in localized disease or in the case of biochemical recurrence (BCR). Improved knowledge of PC biology and ADT resistance mechanisms have led to the development of novel generation androgen receptor pathway inhibitors (ARPI). Initially used only in patients who became resistant to ADT, ARPI have subsequently shown to be effective when used in patients with metastatic hormone-naive disease and in recent years their effectiveness has also been evaluated in localized disease and in case of BCR. The objective of this review is to describe the current role of agents interfering with the androgen receptor in different stages of PC and to point out future perspectives.

Natural History and Real-World Treatment Outcomes for Patients With NSCLC Having EGFR Exon 20 Insertion Mutation: An International Association for the Study of Lung Cancer-American Society of Clinical Oncology CancerLinQ Study.

Introduction: EGFR exon 20 insertion (ex20ins) mutations account for approximately 10% of EGFR mutations in lung adenocarcinoma. Patients with ex20ins mutation do not respond to standard EGFR tyrosine kinase inhibitor therapy. In this work, we analyzed the characteristics, treatment patterns, and outcomes in this subgroup of patients with NSCLC. Methods: The American Society of Clinical Oncology CancerLinQ Discovery data set was queried to identify patients with initial diagnosis of NSCLC between the years 1995 and 2018 and with EGFR ex20ins mutations. Data were extracted on patient demographics, tumor characteristics, treatments, and outcomes, and compared using chi-square and analysis of variance. Kaplan-Meier curves were generated to compare overall survival with log-rank tests. All analyses were performed using Python 3.6 (Python Software Foundation). Results: A total of 357 patients were eligible. Patient characteristics include a median age of 68 years comprising female sex of 54%, White race of 63%, and Black race of 9%. Approximately 62% of total patients had stage 4 disease, and 30% of all patients had brain metastasis. There were 54% of patients who were treated with chemotherapy and 15% with immune checkpoint inhibitors (ICIs). In patients with brain metastasis, 16% were treated with ICI, 18% with targeted therapy, and 59% with chemotherapy. The median survival of the entire group was 23.8 months. Among patients with stage 4 disease (n = 222): 51% were women, 64% were white, 37% had brain metastasis, 18% were treated with ICI, 14% had targeted therapy, and 60% were treated with chemotherapy. Stage 4 patients treated with targeted therapy had better survival compared with those who did not receive targeted therapy (20.6 versus 16.1 mo, p = 0.02). Univariate and multivariate analyses suggested favorable outcomes for patients treated with immunotherapy. Conclusions: EGFR ex20ins mutation represents a unique subset of NSCLC; it is associated with a higher propensity for brain metastases and a relatively modest overall survival. Novel treatment approaches are urgently needed to improve patient outcomes.

Epigenetic determinants in soft tissue sarcomas: molecular mechanisms and therapeutic targets.

INTRODUCTION: Soft tissue sarcomas are a group of rare, mesenchymal tumors characterized by dismal prognosis in advanced/metastatic stages. Knowledge of their molecular determinants is still rather limited. However, in recent years, epigenetic regulation - the modification of gene expression/function without DNA sequence variation - has emerged as a key player both in sarcomagenesis and sarcoma progression. AREAS COVERED: Herein, we describe and review the main epigenetic mechanisms involved in chromatin remodeling and their role as disease drivers in different soft tissue sarcoma histotypes, focusing on epithelioid sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. Focusing on chromatin-remodeling complexes, we provide an in-depth on the role of BAF complex alterations in these soft tissue sarcoma histotypes. In parallel, we highlight current state-of-the-art and future perspectives in the development of rational, innovative treatments leveraging on epigenetic dysregulation in soft tissue sarcomas. EXPERT OPINION: Therapeutic options for metastatic/advanced sarcomas are to date very limited and largely represented by cytotoxic agents, with only modest results. In the continuous attempt to find novel targets and innovative, effective drugs, epigenetic mechanisms represent an emerging and promising field of research, especially for malignant peripheral nerve sheath tumors, epithelioid and synovial sarcoma.

The International Association for the Study of Lung Cancer Early Lung Imaging Confederation Open-Source Deep Learning and Quantitative Measurement Initiative.

INTRODUCTION: With global adoption of computed tomography (CT) lung cancer screening, there is increasing interest to use artificial intelligence (AI) deep learning methods to improve the clinical management process. To enable AI research using an open-source, cloud-based, globally distributed, screening CT imaging data set and computational environment that are compliant with the most stringent international privacy regulations that also protect the intellectual properties of researchers, the International Association for the Study of Lung Cancer sponsored development of the Early Lung Imaging Confederation (ELIC) resource in 2018. The objective of this report is to describe the updated capabilities of ELIC and illustrate how this resource can be used for clinically relevant AI research. METHODS: In this second phase of the initiative, metadata and screening CT scans from two time points were collected from 100 screening participants in seven countries. An automated deep learning AI lung segmentation algorithm, automated quantitative emphysema metrics, and a quantitative lung nodule volume measurement algorithm were run on these scans. RESULTS: A total of 1394 CTs were collected from 697 participants. The LAV950 quantitative emphysema metric was found to be potentially useful in distinguishing lung cancer from benign cases using a combined slice thickness more than or equal to 2.5 mm. Lung nodule volume change measurements had better sensitivity and specificity for classifying malignant from benign lung nodules when applied to solid lung nodules from high-quality CT scans. CONCLUSIONS: These initial experiments revealed that ELIC can support deep learning AI and quantitative imaging analyses on diverse and globally distributed cloud-based data sets.

Niraparib plus Dostarlimab in Pleural Mesothelioma or Non-Small Cell Lung Cancer Harboring HRR Mutations: Interim Results of the UNITO-001 Phase II Prospective Trial.

PURPOSE: Treatment of homologous recombination repair-deficient (HRD)-tumors with PARP inhibitors has the potential to further increase tumor immunogenicity, suggesting a synergistic effect with immunotherapy. Here we present the preliminary results of niraparib in combination with dostarlimab for pleural mesothelioma (PM) or non-small cell lung cancer (NSCLC) harboring HRR mutations. PATIENTS AND METHODS: UNITO-001 is a phase II, prospective, study aiming to investigate the combination of niraparib plus dostarlimab in pretreated patients with HRD and programmed death ligand-1 (PD-L1) ≥1% NSCLC and/or PM. The primary endpoint is progression-free survival (PFS). RESULTS: Seventeen of 183 (10%) screened patients (12 PM and 5 NSCLC) were included. The objective response rate (ORR) was 6% [95% confidence interval (CI): 0.1-28.7] and the disease control rate (DCR) was 53% (95% CI: 27.8-77). Median PFS was 3.1 (95% CI: 2.7-N.A) and median overall survival (OS) was 4.2 (95% CI: 1.58-NA) months. The PFS was 14.1 months in one PM patient harboring a germline BAP1 mutation. The treatment duration was 9.8 months in one PM patient harboring a somatic BRCA2 mutation. The most common adverse events (AE) were grade 1-2 lymphopenia (59%), anemia (35%), hyponatremia (29%), and hypokalemia (29%). Grade ≥3 AEs were reported in 23% of the patients. CONCLUSIONS: This preliminary analysis highlighted the lack of antitumor activity for the combination of niraparib and dostarlimab in patients with PM and/or advanced NSCLC harboring BAP1 somatic mutations. A potential antitumor activity emerged for PM with germline BAP1 and/or BRCA2 somatic mutations along with a good tolerability profile.

Platinum-based chemotherapy attenuates the effector response of CD8 T cells to concomitant PD-1 blockade.

PURPOSE: Combination of chemotherapy (CT) with programmed cell death (PD)-1 blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how CT affects the response of exhausted CD8 T cells to PD-1 blockade. EXPERIMENTAL DESIGN: We used the well-established mouse model of T cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of CT (cisplatin+pemetrexed) on T cell response to PD-1 blockade, in the absence of the impact of CT on antigen release and presentation observed in tumor models. RESULTS: When concomitantly administered with PD-1 blockade, CT affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of interferon (IFN)-γ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared to PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed CT, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by CT partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant CT, ultimately resulting in impaired overall CD8 T cell effector functions. CONCLUSIONS: In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T cell functions.

The Role of Germline Mutations in Thoracic Malignancies: Between Myth and Reality.

Considering the established contribution of environmental factors to the development of thoracic malignancies, the inherited susceptibility of these tumors has rarely been explored. However, the recent introduction of next-generation sequencing-based tumor molecular profiling in the real-word setting enabled us to deeply characterize the genomic background of patients with lung cancer with or without smoking-related history, increasing the likelihood of detecting germline mutations with potential prevention and treatment implications. Pathogenic germline variants have been detected in 2% to 3% of patients with NSCLC undergoing next-generation sequencing analysis, whereas the proportion of germline mutations associated with the development of pleural mesothelioma widely varies across different studies, ranging between 5% and 10%. This review provides an updated summary of emerging evidence about germline mutations in thoracic malignancies, focusing on pathogenetic mechanisms, clinical features, therapeutic implications, and screening recommendations for high-risk individuals.

Autocrine 17-ß-Estradiol/Estrogen Receptor-α Loop Determines the Response to Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer.

PURPOSE: The response to immune checkpoint inhibitors (ICI) often differs between genders in non-small cell lung cancer (NSCLC), but metanalyses results are controversial, and no clear mechanisms are defined. We aim at clarifying the molecular circuitries explaining the differential gender-related response to anti-PD-1/anti-PD-L1 agents in NSCLC. EXPERIMENTAL DESIGN: We prospectively analyzed a cohort of patients with NSCLC treated with ICI as a first-line approach, and we identified the molecular mechanisms determining the differential efficacy of ICI in 29 NSCLC cell lines of both genders, recapitulating patients' phenotype. We validated new immunotherapy strategies in mice bearing NSCLC patient-derived xenografts and human reconstituted immune system ("immune-PDXs"). RESULTS: In patients, we found that estrogen receptor α (ERα) was a predictive factor of response to pembrolizumab, stronger than gender and PD-L1 levels, and was directly correlated with PD-L1 expression, particularly in female patients. ERα transcriptionally upregulated CD274/PD-L1 gene, more in females than in males. This axis was activated by 17-ß-estradiol, autocrinely produced by intratumor aromatase, and by the EGFR-downstream effectors Akt and ERK1/2 that activated ERα. The efficacy of pembrolizumab in immune-PDXs was significantly improved by the aromatase inhibitor letrozole, which reduced PD-L1 and increased the percentage of antitumor CD8+T-lymphocytes, NK cells, and Vγ9Vδ2 T-lymphocytes, producing durable control and even tumor regression after continuous administration, with maximal benefit in 17-ß-estradiol/ERα highfemale immune-xenografts. CONCLUSIONS: Our work unveils that 17-ß-estradiol/ERα status predicts the response to pembrolizumab in patients with NSCLC. Second, we propose aromatase inhibitors as new gender-tailored immune-adjuvants in NSCLC. See related commentary by Valencia et al., p. 3832.

Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non-Small-Cell Lung Cancer.

PURPOSE: Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS: This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS: Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common. CONCLUSION: In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Exploring circular MET RNA as a potential biomarker in tumors exhibiting high MET activity.

BACKGROUND: MET-driven acquired resistance is emerging with unanticipated frequency in patients relapsing upon molecular therapy treatments. However, the determination of MET amplification remains challenging using both standard and next-generation sequencing-based methodologies. Liquid biopsy is an effective, non-invasive approach to define cancer genomic profiles, track tumor evolution over time, monitor treatment response and detect molecular resistance in advance. Circular RNAs (circRNAs), a family of RNA molecules that originate from a process of back-splicing, are attracting growing interest as potential novel biomarkers for their stability in body fluids. METHODS: We identified a circRNA encoded by the MET gene (circMET) and exploited blood-derived cell-free RNA (cfRNA) and matched tumor tissues to identify, stratify and monitor advanced cancer patients molecularly characterized by high MET activity, generally associated with genomic amplification. RESULTS: Using publicly available bioinformatic tools, we discovered that the MET locus transcribes several circRNA molecules, but only one candidate, circMET, was particularly abundant. Deeper molecular analysis revealed that circMET levels positively correlated with MET expression and activity, especially in MET-amplified cells. We developed a circMET-detection strategy and, in parallel, we performed standard FISH and IHC analyses in the same specimens to assess whether circMET quantification could identify patients displaying high MET activity. Longitudinal monitoring of circMET levels in the plasma of selected patients revealed the early emergence of MET amplification as a mechanism of acquired resistance to molecular therapies. CONCLUSIONS: We found that measurement of circMET levels allows identification and tracking of patients characterized by high MET activity. Circulating circMET (ccMET) detection and analysis could be a simple, cost-effective, non-invasive approach to better implement patient stratification based on MET expression, as well as to dynamically monitor over time both therapy response and clonal evolution during treatment.

Real-world retrospective study of KRAS mutations in advanced non-small cell lung cancer in the era of immunotherapy.

BACKGROUND: KRAS mutation-positive (KRAS-positive), advanced nonsmall-cell lung cancer (NSCLC) is characterized by a poor prognosis. KRAS mutations are extremely heterogeneous from a biologic point of view, and real-world data by mutation subtype in the era of immunotherapy are still incomplete. METHODS: The objective of this study was to retrospectively analyze all consecutive patients with advanced/metastatic, KRAS-positive NSCLC who were diagnosed at a single academic institution since the advent of immunotherapy. The authors report on the natural history of the disease as well as the efficacy of first-line treatments in the entire cohort and by KRAS mutation subtypes as well as the presence/absence of co-mutations. RESULTS: From March 2016 to December 2021, the authors identified 199 consecutive patients who had KRAS-positive, advanced or metastatic NSCLC. The median overall survival (OS) was 10.7 months (95% confidence interval [CI], 8.5-12.9 months), and there were no differences by mutation subtype. Among 134 patients who received first-line treatment, the median OS was 12.2 months (95% CI, 8.3-16.1 months), and the median progression-free survival was 5.6 months (95% CI, 4.5-6.6 months). At multivariate analysis, only an Eastern Cooperative Oncology Group performance status of 2 was associated with significantly shorter progression-free survival and OS. CONCLUSIONS: KRAS-positive, advanced NSCLC is characterized by a poor prognosis despite the introduction of immunotherapy. Survival was not associated with KRAS mutation subtype. PLAIN LANGUAGE SUMMARY: This study evaluated the efficacy of systemic therapies for advanced/metastatic nonsmall cell lung cancer harboring KRAS mutations, along with the potential predictive and prognostic role of mutation subtypes. The authors found that advanced/metastatic, KRAS-positive nonsmall cell lung cancer is characterized by a poor prognosis and that first-line treatment efficacy is not related to different KRAS mutations, although a numerically shorter median progression-free survival was observed in patients who had p.G12D and p.G12A mutations. These results underline the need for novel treatment options in this population, such as next-generation KRAS inhibitors, which are in clinical and preclinical development.

Tumor plasticity and therapeutic resistance in oncogene-addicted non-small cell lung cancer: from preclinical observations to clinical implications.

The identification of actionable targets in oncogene-addicted non-small cell lung cancer (NSCLC) has fueled biomarker-directed strategies, especially in advanced stage disease. Despite the undeniable success of molecular targeted therapies, duration of clinical response is relatively short-lived. While extraordinary efforts have defined the complexity of tumor architecture and clonal evolution at the genetic level, not equal interest has been given to the dynamic mechanisms of phenotypic adaptation engaged by cancer during treatment. At the clinical level, molecular targeted therapy of EGFR-mutant and ALK-rearranged tumors often results in epithelial-to-mesenchymal transition (EMT) and histological transformation of the original adenocarcinoma without the acquisition of additional genetic lesions, thus limiting subsequent therapeutic options and patient outcome. Here we provide an overview of the current understanding of the genetic and non-genetic molecular circuits governing this phenomenon, presenting current strategies and potentially innovative therapeutic approaches to interfere with lung cancer cell plasticity.

Rare thoracic cancers: a comprehensive overview of diagnosis and management of small cell lung cancer, malignant pleural mesothelioma and thymic epithelial tumours.

Despite the progress in outcomes seen with immunotherapy in various malignancies, including nonsmall cell lung cancer, the benefits are less in small cell lung cancer, malignant pleural mesothelioma and thymic epithelial tumours. New effective treatment options are needed, guided via more in-depth insights into the pathophysiology of these rare malignancies. This review comprehensively presents an overview of the clinical presentation, diagnostic tools, staging systems, pathophysiology and treatment options for these rare thoracic cancers. In addition, opportunities for further improvement of therapies are discussed.

Short-Term Safety and Psychosocial Impact of the BNT162b2 mRNA COVID-19 Vaccine in Cancer Patients-An Italian Single-Center Experience.

Safety data regarding BNT162b2 in cancer patients (CPs) are scarce. Herein we report the side effects (SEs), the adverse events (AEs), and the patient-reported outcomes (PROs) following BNT162b2 administration in CPs treated at the San Luigi Gonzaga University Hospital. All CPs who agreed to participate in our vaccination campaign received BNT162b2 and were included in the descriptive analysis. An anonymous questionnaire investigating the occurrence of SEs/AEs and PROs was administered to the study population 21 days after the first dose. Pearson's chi-squared test was used to estimate the risk of experiencing SEs/AEs according to selected variables. A total of 997 patients were included in the study: 62.0% had stage IV cancer, and 68.8% were receiving an active treatment, of whom 15.9% were receiving immunotherapy. SEs/AEs were recorded in 37.1% of cases after the first dose and in 48.5% of cases after the second dose. The most common SEs were muscle pain/local rash (27.9% and 28%, after the first and second dose, respectively). Patients older than 70 years showed lower risk of SEs/AEs, while women showed a higher risk. Before receiving the vaccine, 18.2% of patients felt fearful and/or insecure about the vaccination. After the first dose, 57.5% of patients changed their feelings positively. Our data support the short-term safety of BNT162b2 in CPs, regardless of disease stage and concurrent treatments. Overall, the vaccination showed a positive impact on quality of life.

Therapeutic sequencing in advanced renal cell carcinoma: How to choose considering clinical and biological factors.

In the last fifteen years a better understanding of the biological processes promoting tumour growth and progression led to an impressive revolution in metastatic renal cell carcinoma (mRCC) treatment landscape. Angiogenesis plays a critical role in the pathogenesis of RCC. These biological evidences led to targeted therapies interfering with vascular endothelial growth factor and mammalian target of rapamycin pathway. Another big step in the RCC therapeutic landscape was recently made because of the understanding of the interplay between angiogenesis and immune cells. Dual immune checkpoint inhibitors (ICIs) and ICIs plus tyrosine kinase inhibitors (TKI) combinations have been approved considering overall survival benefit compared to targeted therapies as first line treatment. We summarize the activity and the biological rationale of ICIs combinations as mRCC first line therapy. Additionally, we review the clinical and biological criteria useful to guide clinicians in the choice of treatment sequencing focusing on ICIs combinations resistance mechanisms.

Role of radium-223 discontinuation due to adverse events in castration-resistant prostate cancer patients. A retrospective monocentric analysis.

BACKGROUND: Radium 223 (Ra-223) was approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) patients with bone-only disease, following demonstration of significant improvement in overall survival (OS). To date, there are no validated prognostic factors useful in predicting outcome of mCRPC patients treated with Ra-223. Our retrospective study aims to evaluate the prognostic role of treatment discontinuation due to adverse events in mCRPC patients treated with Ra-223, and to identify which factors correlate with the toxicity onset. METHODS: We performed a retrospective analysis of all consecutive mCRPC patients treated with Ra-223 from September 2013 to December 2019 at our institute. Patients were divided in 2 groups according to the reason of Ra-223 therapy discontinuation: toxicity versus other causes. Outcome measures were progression-free survival (PFS) and OS. RESULTS: In the overall population (75 patients) median PFS and OS were 5.46 months and 11.15 months respectively. Patients who discontinued treatment due to toxicity had a lower median PFS (3.49 vs 5.89 months, HR: 1.88, 95% CI: 1.14-3.12, p = 0.014) and OS (8.59 vs 14.7 months HR: 3.33, 95% CI: 1.85-6.01, p < 0.001) than patients who discontinued therapy due to other causes. The risk of Ra-223 discontinuation due to toxicity correlates with the number of previous treatments (p = 0.002), previous chemotherapy treatment (p = 0.039), baseline LDH (p = 0.012), Hb (p = 0.021) and platelet-to-lymphocyte ratio (p = 0.024). CONCLUSIONS: Discontinuation due to toxicity is associated with worse outcomes in mCRPC patients treated with Ra-223. To reduce the risk of developing toxicities that may compromise treatment efficacy, Ra-223 should be used early in mCRPC patients.

Novel Lymphocyte-Independent Antitumor Activity by PD-1 Blocking Antibody against PD-1+ Chemoresistant Lung Cancer Cells.

PURPOSE: Antibodies against the lymphocyte PD-1 (aPD-1) receptor are cornerstone agents for advanced non-small cell lung cancer (NSCLC), based on their ability to restore the exhausted antitumor immune response. Our study reports a novel, lymphocyte-independent, therapeutic activity of aPD-1 against NSCLC, blocking the tumor-intrinsic PD-1 receptors on chemoresistant cells. EXPERIMENTAL DESIGN: PD-1 in NSCLC cells was explored in vitro at baseline, including stem-like pneumospheres, and following treatment with cisplatin both at transcriptional and protein levels. PD-1 signaling and RNA sequencing were assessed. The lymphocyte-independent antitumor activity of aPD-1 was explored in vitro, by PD-1 blockade and stimulation with soluble ligand (PD-L1s), and in vivo within NSCLC xenograft models. RESULTS: We showed the existence of PD-1+ NSCLC cell subsets in cell lines and large in silico datasets (Cancer Cell Line Encyclopedia and The Cancer Genome Atlas). Cisplatin significantly increased PD-1 expression on chemo-surviving NSCLC cells (2.5-fold P = 0.0014), while the sequential treatment with anti-PD-1 Ab impaired their recovery after chemotherapy. PD-1 was found to be associated with tumor stemness features. PD-1 expression was enhanced in NSCLC stem-like pneumospheres (P < 0.0001), significantly promoted by stimulation with soluble PD-L1 (+27% ± 4, P < 0.0001) and inhibited by PD-1 blockade (-30% ± 3, P < 0.0001). The intravenous monotherapy with anti-PD-1 significantly inhibited tumor growth of NSCLC xenografts in immunodeficient mice, without the contribution of the immune system, and delayed the occurrence of chemoresistance when combined with cisplatin. CONCLUSIONS: We report first evidence of a novel lymphocyte-independent activity of anti-PD-1 antibodies in NSCLC, capable of inhibiting chemo-surviving NSCLC cells and exploitable to contrast disease relapses following chemotherapy. See related commentary by Augustin et al., p. 505.

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1.

BACKGROUND: Talazoparib has shown antitumor activity with a manageable safety profile in men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR)/homologous recombination repair (HRR) alterations. OBJECTIVE: To evaluate patient-reported health-related quality of life (HRQoL) and pain in patients who received talazoparib in the TALAPRO-1 study, with a special interest in patients harboring breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. DESIGN, SETTING, AND PARTICIPANTS: TALAPRO-1 is a single-arm, phase 2 study in men with mCRPC DDR alterations either directly or indirectly involved in HRR, who previously received one to two taxane-based chemotherapy regimens for advanced prostate cancer and whose mCRPC progressed on one or more novel hormonal agents. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Men completed the European Quality-of-life Five-dimension Five-level scale (EQ-5D-5L), EQ-5D visual analog scale (VAS), and Brief Pain Inventory-Short Form at predefined time points during the study. The patient-reported outcome (PRO) population included men who completed a baseline and one or more postbaseline assessments before study end. Longitudinal mixed-effect models assuming an unstructured covariance matrix were used to estimate the mean (95% confidence interval [CI]) change from baseline for pain and general health status measurements among all patients and patients with BRCA1/2 mutations. RESULTS AND LIMITATIONS: In the 97 men in the PRO population treated with talazoparib (BRCA1/2, n = 56), the mean (95% CI) EQ-5D-5L Index improved (all patients, 0.05 [0.01, 0.08]; BRCA1/2 subset, 0.07 [0.03, 0.10]), as did the EQ-5D VAS scores (all patients, 5.42 [2.65, 8.18]; BRCA1/2 subset, 4.74 [1.07, 8.41]). Improvements in the estimated overall change from baseline (95% CI) in the mean worst pain were observed in all patients (-1.08 [-1.52, -0.65]) and the BRCA1/2 subset (-1.15 [-1.67, -0.62]). The probability of not having had experienced deterioration of worst pain by month 12 was 84% for all patients and 83% for the BRCA1/2 subset. CONCLUSIONS: In heavily pretreated men with mCRPC and DDR/HRR alterations, talazoparib was associated with improved HRQoL in all patients and the BRCA1/2 subset. In both patient groups, worst pain improved from baseline and the probability of not experiencing a deterioration in worst pain with talazoparib was high. PATIENT SUMMARY: We show that talazoparib was associated at least with no change or improvements in health-related quality of life (HRQoL) and pain burden in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair gene alterations in the TALAPRO-1 study. These findings in patient-reported HRQoL and pain complement the antitumor activity and tolerability profile of talazoparib.